Targeting Proteasomes in Cancer and Infectious Disease: A Parallel Strategy to Treat Malignancies and Microbes

Abstract

Essential core pathways of cellular biology are preserved throughout evolution, highlighting the importance of these pathways for both bacteria and human cancer cells alike. Cell viability requires a proper balance between protein synthesis and degradation in order to maintain integrity of the proteome. Proteasomes are highly intricate, tightly regulated multisubunit complexes that are critical to achieve protein homeostasis (proteostasis) through the selective degradation of misfolded, redundant and damaged proteins. Proteasomes function as the catalytic core of the ubiquitin-proteasome pathway (UPP) which regulates a myriad of essential processes including growth, survival, differentiation, drug resistance and apoptosis. Proteasomes recognize and degrade proteins that have been marked by covalently attached poly-ubiquitin chains. Deregulation of the UPP has emerged as an essential etiology of many prominent diseases, including cancer. Proteasome inhibitors selectively target cancer cells, including those resistant to chemotherapy, while sparing healthy cells. Proteasome inhibition has emerged as a transformative anti-myeloma strategy that has extended survival for certain patient populations from 3 to 8 years. The structural architecture and functional activity of proteasomes is conserved from Archaea to humans to support the concept that proteasomes are actionable targets that can be inhibited in pathogenic organisms to improve the treatment of infectious diseases. Proteasomes have an essential role during all stages of the parasite life cycle and features that distinguish proteasomes in pathogens from human forms have been revealed. Advancement of inhibitors that target Plasmodium and Mycobacterial proteasomes is a means to improve treatment of malaria and tuberculosis. In addition, PIs may also synergize with current frontline agents support as resistance to conventional drugs continues to increase. The proteasome represents a highly promising, actionable target to combat infectious diseases that devastate lives and livelihoods around the globe.

Keywords: cancer; infection; malaria; myeloma; proteasome; tuberculosis.

Figure 1

(A) Complexity of the Proteasome Structure Throughout Evolution. The constitutive 20S proteasome is assembled in a (green) and b (yellow) heptameric rings. Constitutive 20S proteasomes (c20S) contain the catalytic subunits b1, b2 and b5. The 20S immunoproteasome (i20S) catalytic core contains three inducible b subunits named b1i, b2i and b5i. immunoproteasomes As previously described, intracellular proteasomes can exist in multiple different forms (Gomes, 2013). Both c20S and i20S proteasomes are found with or without regulators. The c20S is capped at one or both ends by a 19S RP (light brown) to form 26S or 30S proteasomes. The i20S proteasome is capped by either the PA28ab or PA28g complex at either one or both ends. Hybrid proteasome complexes are also found when the catalytic core is simultaneously associated with 19S RP and another type of regulator, e.g., PA28ab, PA28g, PA200. In the cytoplasm ECM29 and PSMF1 can modify the assembly or activity of the proteasome; while in the nucleus PA200 can regulate proteasome activity. (B) Cross-sectional View of Proteasome 20S Core Particles. Shown is a cross-sectional side view of 20S proteasomes showing the evolutionarily conserved barrel-like (a7b7b7a7) structure in eubacterial and eukaryotic proteasomes. Archaea and Mtb proteasomes are depicted as having seven identical b subunits, whereas eukaryotic proteasomes have seven different b subunits. In lymphoid cells and spleen, constitutive 20S proteasome catalytic subunits b1, b2 and b5 are substituted by three inducible b subunits named b1i, b2i and b5i to generate 20S proteasomes. 26S proteasomes exist with either one or two 19S caps, immunoproteasomes containing one or two 11S caps, proteasomes containing the 20S proteasome with one or two PA200 caps (in the nucleus only), and hybrid proteasomes which contain different combinations of 20S and activators.